Quadrivalent Influenza Vaccine Research Articles

Relative Effectiveness of MF59 Adjuvanted Trivalent Influenza Vaccine vs Nonadjuvanted Vaccines During the 2019-2020 Influenza Season.

BackgroundAge-related immunosenescence may impair the immune response to vaccination in older adults. Adjuvanted influenza vaccines are designed to overcome immune senescence in older adults. This study estimated the relative vaccine effectiveness (rVE) of MF59-adjuvanted trivalent inactivated influenza vaccine (aIIV3) vs egg-derived quadrivalent inactivated influenza vaccine (IIV4e) and high-dose trivalent inactivated influenza vaccine (HD-IIV3) in preventing influenza-related medical encounters in the 2019–2020 US season.MethodsThis retrospective cohort study used electronic medical records linked to pharmacy and medical claims data. The study population included adults age ≥65 years with a record of aIIV3, IIV4e, or HD-IIV3 vaccination. A doubly robust inverse probability of treatment weighting model was used to derive adjusted odds ratios (ORs). rVE was calculated by (1 – ORadjusted)*100 and was determined overall and separately for age subgroups. An exploratory analysis evaluated the outcome separately in inpatient and outpatient settings.ResultsSubjects received aIIV3 (n = 936 508), IIV3e (n = 651 034), and HD-IIV3 (n = 1 813 819), and influenza-related medical encounters were recorded in 0.5%, 0.9%, and 0.7% of each cohort, respectively. Overall, the rVE of aIIV3 was 27.5% (95% CI, 24.4% to 30.5%) vs IIV4e and 13.9% (95% CI, 10.7% to 17.0%) vs HD-IIV3. aIIV3 had a more favorable rVE in inpatient and outpatient settings. Findings remained consistent across age subgroups and during alternative seasonal dates.ConclusionsAdults age ≥65 years vaccinated with aIIV3 had fewer influenza-related medical encounters compared with IIV4e or HD-IIV3 during the 2019–2020 US influenza season.

Cell-based flu vaccine could be more effective in preventing the flu

A new retrospective analysis by Divino and colleagues published in the January 2022 issue of Open Forum Infectious Diseases found that cell-derived quadrivalent influenza vaccines (IIV4c) are significantly more effective than standard egg-derived quadrivalent influenza vaccines (IIV4e) at preventing influenza-related hospitalizations or ED visits, which is also associated with lower overall health care costs. Most influenza vaccines in the United States are manufactured using a traditional egg-based process, which is the standard of care and plays a critical role in influenza prevention. Based on the study’s initial sample of recipients, 79.3% (6,578,855 out of 8,300,292) of the study participants received IIV4e, while 20.7% (1,721,437 out of 8,300,292) received IIV4c during the study period of August 2019 to January 2020. “The IIV4e process can cause the influenza strain to mutate, which may lead to an antigenic mismatch between the circulating strains and the inactivated strains contained within the seasonal influenza vaccine,” said Victoria Divino, the study’s lead investigator. “This can result in reduced vaccine effectiveness, particularly for influenza A(H3N2) viruses.” The study used the IQVIA PharMetrics Plus administrative claims database to investigate influenza-related hospitalizations or ED visits and other clinical outcomes postvaccination classified by diagnosis codes during the 2019–2020 influenza season (beginning August 4, 2019, and ending March 7, 2020). Inverse probability of treatment weighting (IPTW)–weighted multivariate Poisson regression models were developed to estimate adjusted rate ratios (RRs) for IIV4c compared to IIV4e to estimate the adjusted average treatment effect, or the effect of treatment in the entire study population. Adjusted rVE was calculated as (1-RR)*100%. After applying eligibility criteria and IPTW adjustment, 1,150,134 and 3,924,819 participants aged 4 to 64 years received IIV4c and IIV4e, respectively. Comorbidities were evaluated at baseline, and vaccine cohorts were well-balanced on all measured confounders post-IPTW, including baseline comorbidity, said Divino, who is an associate principal at IQVIA, a data science company in Durham, NC. Clinical outcomes and all-cause costs were evaluated separately in this study post-IPTW. Divino and colleague’s study results demonstrate that IIV4c was significantly more effective than IIV4e in preventing influenza-related hospitalizations or ED visits, with an adjusted relative vaccine effectiveness (rVE) of 5.3% during a high influenza activity period between December 8, 2019, and March 7, 2020. Adjusted rVE was significantly higher for IIV4c in preventing hospitalizations/ED visits concerning any respiratory event (8.2%), pneumonia (6.7%), or asthma/COPD/bronchial events (7.6%), according to the study. IIV4c was also associated with significantly lower annualized all-cause costs postvaccination—with a difference of $467 per participant—than IIV4e, which Divino said is driven by lower costs for outpatient medical services and inpatient hospitalizations. Although IPTW was used to adjust for imbalances in measured confounders between the cohorts, which were well-balanced post-IPTW, it is possible that imbalances remained due to potential unmeasured confounding variables, according to Divino. “Unfortunately, the utilized database does not include information on socioeconomic status, race, or culture,” said Divino. “Also, the study sample was largely commercially insured or self-insured, so these findings may not be representative of the uninsured or Medicaid populations,” Divino noted, indicating that additional research is needed among uninsured and Medicaid populations. Given a choice between IIV4c and IIV4e influenza vaccine options, the findings demonstrate that the adjusted rVE of IIV4c is significantly better than that of IIV4e in preventing influenza-related hospitalizations/ED visits. IIV4c is also associated with significant cost savings.

The New Quadrivalent Adjuvanted Influenza Vaccine for the Italian Elderly: A Health Technology Assessment.

Background. The elderly, commonly defined as subjects aged ≥65 years, are among the at-risk subjects recommended for annual influenza vaccination in European countries. Currently, two new vaccines are available for this population: the MF59-adjuvanted quadrivalent influenza vaccine (aQIV) and the high-dose quadrivalent influenza vaccine (hdQIV). Their multidimensional assessment might maximize the results in terms of achievable health benefits. Therefore, we carried out a Health Technology Assessment (HTA) of the aQIV by adopting a multidisciplinary policy-oriented approach to evaluate clinical, economic, organizational, and ethical implications for the Italian elderly. Methods. A HTA was conducted in 2020 to analyze influenza burden; characteristics, efficacy, and safety of aQIV and other available vaccines for the elderly; cost-effectiveness of aQIV; and related organizational and ethical implications. Comprehensive literature reviews/analyses were performed, and a transmission model was developed in order to address the above issues. Results. In Italy, the influenza burden on the elderly is high and from 77.7% to 96.1% of influenza-related deaths occur in the elderly. All available vaccines are effective and safe; however, aQIV, such as the adjuvanted trivalent influenza vaccine (aTIV), has proved more immunogenic and effective in the elderly. From the third payer’s perspective, but also from the societal one, the use of aQIV in comparison with egg-based standard QIV (eQIV) in the elderly population is cost-effective. The appropriateness of the use of available vaccines as well as citizens’ knowledge and attitudes remain a challenge for a successful vaccination campaign. Conclusions. The results of this project provide decision-makers with important evidence on the aQIV and support with scientific evidence on the appropriate use of vaccines in the elderly.

Switching from trivalent to quadrivalent inactivated influenza vaccines in Uruguay: a cost-effectiveness analysis

ABSTRACT We evaluated the cost-utility of replacing trivalent influenza vaccine (TIV) with quadrivalent influenza vaccine (QIV) in the current target populations in Uruguay. An existing decision-analytic static cost-effectiveness model was adapted for Uruguay. The population was stratified into age groups. Costs and outcomes were estimated for an average influenza season, based on observed rates from 2013 to 2019 inclusive. Introducing QIV instead of TIV in Uruguay would avoid around 740 additional influenza cases, 500 GP consultations, 15 hospitalizations, and three deaths, and save around 300 workdays, for the same vaccination coverage during an average influenza season. Most of the influenza-related consultations and hospitalizations would be avoided among children ≤4 and adults ≥65 years of age. Using QIV rather than TIV would cost an additional ~US$729,000, but this would be partially offset by savings in consultations and hospitalization costs. The incremental cost per quality-adjusted life-year (QALY) gained with QIV would be in the order of US$18,000 for both the payor and societal perspectives, for all age groups, and around US$12,000 for adults ≥65 years of age. The main drivers influencing the incremental cost-effectiveness ratio were the vaccine efficacy against the B strains and the percentage of match each season with the B strain included in TIV. Probabilistic sensitivity analysis showed that switching to QIV would provide a favorable cost-utility ratio for 50% of simulations at a willingness-to-pay per QALY of US$20,000. A switch to QIV is expected to be cost-effective for the current target populations in Uruguay, particularly for older adults.

Adverse Events of Interest Following Influenza Vaccination in the First Season of Adjuvanted Trivalent Immunization: Retrospective Cohort Study.

BackgroundVaccination is the most effective form of prevention of seasonal influenza; the United Kingdom has a national influenza vaccination program to cover targeted population groups. Influenza vaccines are known to be associated with some common minor adverse events of interest (AEIs), but it is not known if the adjuvanted trivalent influenza vaccine (aTIV), first offered in the 2018/2019 season, would be associated with more AEIs than other types of vaccines.ObjectiveWe aim to compare the incidence of AEIs associated with different types of seasonal influenza vaccines offered in the 2018/2019 season.MethodsWe carried out a retrospective cohort study using computerized medical record data from the Royal College of General Practitioners Research and Surveillance Centre sentinel network database. We extracted data on vaccine exposure and consultations for European Medicines Agency–specified AEIs for the 2018/2019 influenza season. We used a self-controlled case series design; computed relative incidence (RI) of AEIs following vaccination; and compared the incidence of AEIs associated with aTIV, the quadrivalent influenza vaccine, and the live attenuated influenza vaccine. We also compared the incidence of AEIs for vaccinations that took place in a practice with those that took place elsewhere.ResultsA total of 1,024,160 individuals received a seasonal influenza vaccine, of which 165,723 individuals reported a total of 283,355 compatible symptoms in the 2018/2019 season. Most AEIs occurred within 7 days following vaccination, with a seasonal effect observed. Using aTIV as the reference group, the quadrivalent influenza vaccine was associated with a higher incidence of AEIs (RI 1.46, 95% CI 1.41-1.52), whereas the live attenuated influenza vaccine was associated with a lower incidence of AEIs (RI 0.79, 95% CI 0.73-0.83). No effect of vaccination setting on the incidence of AEIs was observed.ConclusionsRoutine sentinel network data offer an opportunity to make comparisons between safety profiles of different vaccines. Evidence that supports the safety of newer types of vaccines may be reassuring for patients and could help improve uptake in the future.

Safety of Live Attenuated Influenza Vaccine in Children With Asthma.

Asthma is considered a precaution for use of quadrivalent live attenuated influenza vaccine (LAIV4) in persons aged ≥5 years because of concerns for wheezing events. We evaluated the safety of LAIV4 in children with asthma, comparing the proportion of children with asthma exacerbations after LAIV4 or quadrivalent inactivated influenza vaccine (IIV4). We enrolled 151 children with asthma, aged 5 to 17 years, during 2 influenza seasons. Participants were randomly assigned 1:1 to receive IIV4 or LAIV4 and monitored for asthma symptoms, exacerbations, changes in peak expiratory flow rate (PEFR), and changes in the asthma control test for 42 days after vaccination. We included 142 participants in the per-protocol analysis. Within 42 days postvaccination, 18 of 142 (13%) experienced an asthma exacerbation: 8 of 74 (11%) in the LAIV4 group versus 10 of 68 (15%) in the IIV4 group (LAIV4-IIV4 = -0.0390 [90% confidence interval -0.1453 to 0.0674]), meeting the bounds for noninferiority. When adjusted for asthma severity, LAIV4 remained noninferior to IIV4. There were no significant differences in the frequency of asthma symptoms, change in PEFR, or childhood asthma control test/asthma control test scores in the 14 days postvaccination between LAIV4 and IIV4 recipients. Vaccine reactogenicity was similar between groups, although sore throat (P = .051) and myalgia (P <.001) were more common in the IIV4 group. LAIV4 was not associated with increased frequency of asthma exacerbations, an increase in asthma-related symptoms, or a decrease in PEFR compared with IIV4 among children aged 5 to 17 years with asthma.

Efficacy and safety of a quadrivalent influenza vaccine in children aged 6–35 months: A global, multiseasonal, controlled, randomized Phase III study

BackgroundChildren are an important target group for influenza vaccination, but few studies have prospectively evaluated influenza vaccine efficacy (VE) in children under 3 years of age. This was a randomized Phase III trial to assess the efficacy, immunogenicity, and safety of an inactivated quadrivalent influenza vaccine (QIV) in young children (EudraCT: 2016–004904–74). MethodsInfluenza-naïve children aged 6–35 months were randomized during three influenza seasons to receive vaccination with QIV or a non-influenza control vaccine. One group of participants was revaccinated with QIV in the subsequent influenza season. The primary efficacy endpoint was the absolute VE of QIV against influenza caused by any circulating strain. Key secondary efficacy endpoints included the absolute VE of QIV against influenza due to antigenically matching strains and immunogenicity. Safety and reactogenicity were also evaluated. ResultsIn total, 1005 children received QIV and 995 received control vaccine. Influenza A/B infection due to any circulating influenza strain occurred less frequently in children who received QIV versus children receiving a control vaccine. The absolute VE of QIV against any circulating influenza strain was 54% (95% confidence interval [CI]: 37%, 66%). The absolute VE of QIV against antigenically matching influenza strains was 68% (95% CI: 45%, 81%). Mean hemagglutination inhibition titers for all influenza strains in the QIV group increased post-vaccination, whereas increases were minimal in the control vaccine group; results from virus neutralization and neuraminidase-inhibition assays were generally consistent with the hemagglutination inhibition assay findings. Approximately 12 months after primary vaccination with QIV, antibody titers remained higher than pre-vaccination titers for most strains. In participants who were revaccinated, QIV elicited strong antibody responses. The overall safety profile and reactogenicity of QIV was comparable with control vaccine. ConclusionPrimary vaccination with QIV was well tolerated and effective in protecting children aged 6–35 months against influenza.

Efficacy and safety of a universal influenza A vaccine (MVA-NP+M1) in adults when given after seasonal quadrivalent influenza vaccine immunisation (FLU009): a phase 2b, randomised, double-blind trial

In animal, epidemiological, and human challenge studies, a pre-existing T-cell response to internal proteins of influenza A has been associated with improved virological and disease outcomes. The aim of this study was to assess whether inducing additional responses to conserved CD4 and CD8 T-cell antigens provides added benefit to standard influenza vaccination. We designed a phase 2b, randomised, placebo-controlled, double-blind trial of a recombinant viral-vectored vaccine (modified vaccinia Ankara expressing virus nucleoprotein and matrix protein 1; MVA-NP+M1), which has been shown to induce both CD4 and CD8 T cells, at eight outpatient clinical trial sites in Australia over two consecutive influenza seasons. We recruited non-immunosuppressed adults (≥18 years) who had received the 2019 quadrivalent influenza vaccine (QIV) vaccine within 28 days before study enrolment and randomisation (day 0). Participants were randomly assigned (1:1) according to a computer-generated random sequence to receive one dose of 1·5 × 108 plaque-forming units of MVA-NP+M1 or saline (placebo) intramuscularly. Randomisation was stratified by age (<65 years or ≥65 years). The patients and trial assessors were masked to treatment assignment. During the subsequent influenza seasons, participants with symptoms related to respiratory illness or influenza-like illness were to attend the clinic within 72 h of symptom onset for two nasal swabs for influenza testing by quantitative RT-PCR. The primary endpoint was the incidence rate of laboratory-confirmed influenza in the intention-to-treat (ITT) population. Safety (solicited adverse events within 7 days and unsolicited adverse events within 28 days after study vaccination, and serious adverse events for the study duration) was assessed in all randomly assigned participants who received at least one vaccination (according to the treatment received). The trial is registered with ClinicalTrials.gov, NCT03880474. Between April 2 and June 14, 2019, 2152 adults were randomly allocated and received MVA-NP+M1 (n=1077) or placebo (n=1075), comprising the efficacy (ITT) analysis set. Participants were followed up throughout the 2019 Australia influenza season (May 1 to Oct 15, 2019). 419 (19·5%) of 2152 participants were aged 65 years or older. The incidence of laboratory-confirmed influenza did not differ between the MVA-NP+M1 group (35 of 1077 participants; 3·25% [95% CI 2·31-4·44]) and the placebo group (23 of 1075; 2·14% [1·39-3·14]; Fisher's exact p=0·14). 23 severe solicited local injection site reactions were reported in 13 (0·6%) of 2152 participants, 22 of which were reported in the MVA-NP + M1 group (in 12 [1·1%] participants). 100 severe systemic events were reported in 45 (4·2%) MVA-NP + M1 recipients, and 20 were reported in 14 (1·3%) placebo recipients. Three unsolicited grade 3 events in three participants (two headache and one nausea, all in the MVA-NP+M1 group) were deemed vaccine related. 21 serious adverse events were reported in 18 (1·7%) of 1077 participants in the MVA-NP+M1 group and 25 serious adverse events were reported in 22 (2·0%) of 1075 participants in the placebo group; none were considered vaccine related. The trial was stopped after one season for futility on the recommendation of the data monitoring committee. MVA-NP+M1 was well tolerated with no vaccine-associated serious adverse events. A vaccine designed to induce moderate T-cell responses to the cross-reactive internal proteins of influenza A did not lead to improved incidence when given within 28 days after standard QIV immunisation. A greater magnitude of T-cell response with a different vaccine or regimen, or localisation in the lungs via alternative delivery, such as intranasal or aerosol, might be successful and require further investigation. Vaccitech.

Universal influenza vaccines are futile when benchmarked against seasonal influenza vaccines

Influenza A viruses pose a challenge for vaccinology in their surface antigenic diversity; however, conserved internal proteins could be used to bolster cellular immunity to provide heterosubtypic immunity. Current influenza vaccines are founded on haemagglutinin antigenic match, and vaccine efficacy can be high when well matched, but more often the matching is subpar and unable to anticipate pandemic and outbreak strains. This shortfall has led to a call for the development of a universal influenza vaccine, 1 Erbelding EJ Post DJ Stemmy EJ et al. A universal influenza vaccine: the strategic plan for the National Institute of Allergy and Infectious Diseases. J Infect Dis. 2018; 218: 347-354 Crossref PubMed Scopus (232) Google Scholar which is proving difficult to accomplish. Efficacy and safety of a universal influenza A vaccine (MVA-NP+M1) in adults when given after seasonal quadrivalent influenza vaccine immunisation (FLU009): a phase 2b, randomised, double-blind trialMVA-NP+M1 was well tolerated with no vaccine-associated serious adverse events. A vaccine designed to induce moderate T-cell responses to the cross-reactive internal proteins of influenza A did not lead to improved incidence when given within 28 days after standard QIV immunisation. A greater magnitude of T-cell response with a different vaccine or regimen, or localisation in the lungs via alternative delivery, such as intranasal or aerosol, might be successful and require further investigation. Full-Text PDF

Seroresponse to Inactivated and Recombinant Influenza Vaccines Among Maintenance Hemodialysis Patients

High-dose influenza vaccine provides better protection against influenza infection in older adults than standard-dose vaccine. We compared vaccine seroresponse among hemodialysis patients over a period of 4 months after administration of high-dose trivalent inactivated (HD-IIV3), standard-dose quadrivalent inactivated (SD-IIV4), or quadrivalent recombinant quadrivalent (RIV4) influenza vaccine. Prospective observational study. Patients at 4 hemodialysis clinics who received influenza vaccine. Type of influenza vaccine. Hemagglutination inhibition (HI) titers were measured at baseline and at 1, 2, 3, and 4 months after vaccination. The primary outcome was seroprotection rates at HI titers of at least 1:40 and at least 1:160 (antibody levels providing protection from infection in approximately 50% and 95% of immunocompetent individuals, respectively) at 1, 2, 3, and 4 months after vaccination. We calculated geometric mean titer as well as seroprotection and seroconversion rates. Adjusted generalized linear models with additional trend analyses were performed to evaluate the association between vaccine type and outcomes. 254 hemodialysis patients were vaccinated against influenza with HD-IIV3 (n= 141), SD-IIV4 (n= 36), or RIV4 (n= 77). A robust initial seroresponse to influenza A strains was observed after all 3 vaccines. Geometric mean titer and seroprotection (HI titer≥1:160) rates against influenza A strains were higher and more sustained with HD-IIV3 than SD-IIV4 or RIV4. More than 80% of patients vaccinated with HD-IIV3 were seroprotected (HI titer≥1:160) at month 4 (P< 0.001), whereas, among patients vaccinated with SD-IIV4 or RIV4, seroprotection rates were similar to those at baseline. Seroprotection rates were lower against B strains for all vaccines. Because of the use of observational data, bias from unmeasured confounders may exist. Some age subgroups were small in number. Clinical outcome data were not available. Hemodialysis patients exhibited high seroprotection rates after all 3 influenza vaccines. The seroresponse waned more slowly with HD-IIV3 compared with SD-IIV4 and RIV4 vaccines.

Systematic review of the efficacy, effectiveness and safety of cell-based seasonal influenza vaccines for the prevention of laboratory-confirmed influenza in individuals ≥18years of age.

The most effective means of preventing seasonal influenza is through strain-specific vaccination. In this study, we investigated the efficacy, effectiveness and safety of cell-based trivalent and quadrivalent influenza vaccines. A systematic literature search was conducted in electronic databases and grey literature sources up to 7 February 2020. Randomised controlled trials (RCTs) and non-randomised studies of interventions (NRSIs) were eligible for inclusion. Two reviewers independently screened, extracted data and assessed the risk of bias of included studies. Certainty of evidence for key outcomes was assessed using the GRADE methodology. The search returned 28,846 records, of which 868 full-text articles were assessed for relevance. Of these, 19 studies met the inclusion criteria. No relative efficacy data were identified for the direct comparison of cell-based vaccines compared with traditional vaccines (egg-based). Efficacy data were available comparing cell-based trivalent influenza vaccines with placebo in adults (aged 18-49years). Overall vaccine efficacy was 70% against any influenza subtype (95% CI 61%-77%, two RCTS), 82% against influenza A(H1N1) (95% CI 71%-89%, 2 RCTs), 72% against influenza A(H3N2) (95% CI 39%-87%, 2 RCTs) and 52% against influenza B (95% CI 30%-68%, 2 RCTs). Limited and heterogeneous data were presented for effectiveness when compared with no vaccination. One NRSI compared cell-based trivalent and quadrivalent vaccination with traditional trivalent and quadrivalent vaccination, finding a small but significant difference in favour of cell-based vaccines for influenza-related hospitalisation, hospital encounters and physician office visits. The safety profile of cell-based trivalent vaccines was comparable to traditional trivalent influenza vaccines. Compared with placebo, cell-based trivalent influenza vaccines have demonstrated greater efficacy in adults aged 18-49years. Overall cell-based vaccines are well-tolerated in adults, however, evidence regarding the effectiveness of these vaccines compared with traditional seasonal influenza vaccines is limited.

Efficacy of a Cell-Based Influenza Vaccine in Children

Source: Nolan T, Fortanier AC, Leav B, et al. Efficacy of a cell-culture-derived quadrivalent influenza vaccine in children. N Engl J Med. 2021;385(16):1485-1495; doi:10.1056/NEJMoa2024848Investigators from multiple institutions conducted a randomized controlled trial to assess the efficacy of a cell-culture-derived quadrivalent inactivated influenza vaccine (IIV4c). Children ages 2 to <18 years from 8 countries: Australia, the Philippines, Thailand, Estonia, Finland, Lithuania, Poland, and Spain, were enrolled from May 25, 2017 to November 5, 2018 and followed during a total of 3 influenza seasons. At enrollment, participants were randomized to receive IIV4c, or a noninfluenza vaccine (meningococcal ACWY [Groups A, C, W-135, and Y] vaccine) as a control. IIV4c was derived from virus grown on Madin-Darby canine kidney cell lines and included 15 µg of hemagglutinin for 2 influenza A subtypes (H1N1 and H3N2) and 2 influenza B lineages (Yamagata and Victoria) per 0.5 mL dose. Parents of participants were contacted weekly and asked about symptoms consistent with influenza-like illness in their child (temperature ≥37.8°C and at least 1 of the following: cough, sore throat, nasal congestion, or rhinorrhea). A nasal swab was obtained on those with influenza-like illness and tested for influenza by PCR and culture. The primary outcome was first occurrence of influenza, confirmed by PCR and/or culture, occurring >14 days after the last vaccination until the end of the influenza season. Secondary outcomes included occurrence of specific influenza subtypes. Cox proportional-hazards models were used to compare occurrence of influenza in those randomized to IIV4c or the control vaccine; age, country, influenza season, and influenza vaccination history were included in the models. Vaccine efficacy was estimated as 1 minus the hazard ratio.A total of 4,514 participants with a mean age of 8.8 ± 4.1 years were enrolled; 50.7% were <9 years old. Among these children, 65.9% were previously vaccinated against influenza. Outcome data were analyzed on 4,509 participants. Overall, a total of 2,186 influenza-like illnesses were reported in 1,576 participants. Nasal swabs for PCR and culture were obtained during 97.4% of these illnesses, and first occurrence of influenza was confirmed in 539 participants, including 231 cases of influenza B (42.9%), 162 cases of influenza A/H3N2 (30.1%), and 126 of influenza A/H1N1 (23.4%). Among those randomized to IIV4c, influenza occurred in 175 of 2,257 participants (7.8%) vs 364 of 2,252 (16.2%) of those randomized to meningococcal ACWY. Overall efficacy of IIV4c was estimated at 54.6% (95% CI, 45.7, 62.1), 58.7% (95% CI, 47.5, 67.5) in children previously vaccinated, and 48.4% (95% CI, 32.1, 60.8) in those previously unvaccinated. Efficacy against A/H1N1, A/H3N2, and type B were 80.7% (95% CI, 69.2, 87.9), 42.1% (95% CI, 20.3, 57.9) and 47.6% (95% CI, 31.4, 60.0), respectively.The authors conclude that IIV4c was effective in preventing influenza.Dr Brady has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.Most pediatric influenza vaccines in the US are manufactured using virus strains grown in eggs (egg-based).1 During growth in eggs, an influenza virus may undergo mutations in the globular head of the hemagglutinin protein, the major epitope.2 Antibodies to the hemagglutinin elicited by egg-based vaccine strains may fail to recognize the hemagglutinin of wild-type influenza strains, even when the vaccine strains and circulating strains are well-matched.3 This has led to low influenza vaccine effectiveness, especially of the H3N2 vaccine strain, in recent seasons.2 Another disadvantage of egg-based influenza vaccines is the long response time to manufacture vaccines when a new influenza virus emerges.4The IIV4c vaccine has been available for adults and children ≥4 years old since 2016.5 In March 2021, approval was extended to children ≥2 years old based on efficacy data from the current study. In October 2021, approval was further extended to infants ≥6 months based on data from a phase 3 randomized controlled study of children aged 6-47 months.6,5Much of the world is still in the throes of a coronavirus pandemic.7 Influenza also has the potential to cause pandemics, which are difficult to predict.1 Newer vaccine platforms (eg, mRNA vaccines as used in SARS-CoV-2 vaccine development) may offer additional protection against influenza.7Cell-culture-derived influenza vaccines have been approved for children ≥6 months. They are safe and effective in preventing influenza in healthy children. (See AAP Grand Rounds. 2022;47[1]:3).8

Safety and immunogenicity of a high-dose quadrivalent influenza vaccine administered concomitantly with a third dose of the mRNA-1273 SARS-CoV-2 vaccine in adults aged ≥65 years: a phase 2, randomised, open-label study

BackgroundConcomitant seasonal influenza vaccination with a COVID-19 vaccine booster could help to minimise potential disruption to the seasonal influenza vaccination campaign and maximise protection against both diseases among individuals at risk of severe disease and hospitalisation. This study aimed to assess the safety and immunogenicity of concomitant administration of high-dose quadrivalent influenza vaccine (QIV-HD) and a mRNA-1273 vaccine booster dose in older adults.MethodsThis study is an ongoing, phase 2, multicentre, open-label, descriptive trial at six clinical research sites in the USA. We describe the interim results up to 21 days after vaccination (July–August, 2021). Community-dwelling adults aged 65 years and older, who were previously vaccinated with a two-dose primary schedule of the mRNA-1273 SARS-CoV-2 vaccine, were eligible for inclusion. The second dose of the primary mRNA-1273 vaccination series was required to have been received at least 5 months before enrolment in the study. Participants were randomly assigned (1:1:1) using a permuted block method stratified by site and by age group (<75 years vs ≥75 years), to receive concomitant administration of QIV-HD and mRNA-1273 vaccine, QIV-HD alone, or mRNA-1273 vaccine alone. Randomisation lists, generated by Sanofi Pasteur biostatistics platform, were provided to study investigators for study group allocation. Unsolicited adverse events occurring immediately, solicited local and systemic reactions up to day 8, and unsolicited adverse events, serious adverse events, adverse events of special interest, and medically attended adverse events up to day 22 were reported. Haemagglutination inhibition antibody responses to influenza A/H1N1, A/H3N2, B/Yamagata, and B/Victoria strains and SARS CoV-2 binding antibody responses (SARS-CoV-2 pre-spike IgG ELISA) were assessed at day 1 and day 22. All analyses were descriptive. The study is registered with ClinicalTrials.gov, NCT04969276.FindingsBetween July 16 and Aug 31, 2021, 306 participants were enrolled and randomly assigned, of whom 296 received at least one vaccine dose (100 in the coadministration group, 92 in the QIV-HD, and 104 in the mRNA-1273 group). Reactogenicity profiles were similar between the coadministration and mRNA-1273 groups, with lower reactogenicity rates in the QIV-HD group (frequency of solicited injection site reactions 86·0% [95% CI 77·6–92·1], 91·3% [84·2–96·0], and 61·8% [50·9–71·9]; frequency of solicited systemic reactions 80·0%, [70·8–87·3], 83·7% [75·1–90·2], and 49·4% [38·7–60·2], respectively). Up to day 22, unsolicited adverse events were reported for 17·0% (95% CI 10·2–25·8) of participants in the coadministration group and 14·4% (8·3–22·7) of participants in the mRNA-1273 group, and tended to be reported at a slightly lower rate (10·9% [5·3–19·1]) in participants in the QIV-HD group. Seven participants each reported one medically attended adverse event (three in the coadministration group, one in the QIV-HD group, and three in the mRNA-1273 group). There were no serious adverse events, adverse events of special interest, or deaths. Haemagglutination inhibition antibody geometric mean titres increased from day 1 to day 22 to similar levels in the coadministration and QIV-HD groups, for each influenza strain (A/H1N1: 363 [95% CI 276–476] vs 366 [272–491]; A/H3N2: 286 [233–352] vs 315 [257–386]; B/Yamagata: 429 [350–525] vs 471 [378–588]; B/Victoria: 377 [325–438] vs 390 [327–465] for the coadministration and QIV-HD groups, respectively). SARS-CoV-2 binding antibody geometric mean concentrations also increased to similar levels in the coadministration and mRNA-1273 groups at day 22 (7634 [95% CI 6445–9042] and 7904 [6883–9077], respectively).InterpretationNo safety concerns or immune interference were observed for concomitant administration of QIV-HD with mRNA-1273 booster in adults aged 65 years and older, supporting co-administration recommendations.FundingSanofi Pasteur.

Emotional Distress, Targeted Rejection, and Antibody Production After Influenza Vaccination in Adolescence.

The purpose of this study was to explore how both ongoing emotional distress and the experience of a targeted rejection over the past 6 months are associated with adolescents' antibody response to influenza virus vaccination. We predicted that experiencing a targeted rejection would amplify the hypothesized negative association between emotional distress and antibody response after vaccination. Adolescent participants (N = 148) completed two study visits (mean [standard deviation] days between visits = 27.4 [1.8]). At the first visit, they provided blood samples, were administered the seasonal (2018-2019) quadrivalent influenza vaccine (Fluzone, Sanofi Pasteur), completed questionnaires, and participated in a semistructured interview. At the second visit, they provided another blood sample. Hemagglutination-inhibition assays were conducted to determine prevaccination and postvaccination antibody titers. Targeted rejection experiences were coded from adolescents' interviews. The emotional distress by targeted rejection interaction predicted antibody response to the two A strains and the composite of all vaccine strains (b values = -0.451 to -0.843, p values < .05), but not the two B strains. Results suggested that, among adolescents who experienced a targeted rejection over the past 6 months, emotional distress was negatively associated with vaccine response (however, this finding did not reach statistical significance). Conversely, among adolescents who did not experience a targeted rejection, emotional distress was positively associated with vaccine response (b = 0.173, p = .032). The current study highlights the importance of evaluating both acute life events and ongoing distress as they relate to adaptive immune functioning in adolescence.

A Prospective Cohort Study on Pregnancy Outcomes in Women Immunized with Seasonal Cell Culture-Derived Quadrivalent Influenza Vaccine (QIVc) During Pregnancy

We conducted a US population-based prospective cohort study designed to collect data on pregnancy outcomes and events of interest among women immunized with QIVc during pregnancy. To overcome the challenges encountered with previous pregnancy registries, a targeted approach using obstetrical clinics that were administering QIVc was employed.

Effectiveness of maternal vaccination with quadrivalent inactivated influenza vaccine in pregnant women and their infants in 2019-2020

ABSTRACT Objectives Influenza is associated with an increased risk for serious illness, hospitalization, and death in pregnant women and young infants. Our aim was to estimate the effectiveness of a quadrivalent inactivated influenza vaccine (QIV) in pregnant women and their infants during 2019–2020. Methods A QIV vaccine was offered to pregnant women followed in a maternity hospital. Women were contacted weekly during the influenza season and asked about symptoms. Polymerase chain reaction testing in pharyngeal samples was offered to pregnant women and infants with influenza-like illness. A Bayesian beta-binomial model was used. Results We studied 636 pregnant women (406 vaccinated and 230 unvaccinated) and 474 infants (281 of mothers vaccinated in pregnancy and 193 of unvaccinated mothers). Using a Bayesian beta-binomial model, it was estimated that influenza vaccination of pregnant women reduced their logit to develop laboratory-confirmed influenza by −4.2 (95% CI −3,7 − 4,7) and the logit of their infants to develop laboratory-confirmed influenza by −4.2 (95% CI −3.6, −4.9). The QIV effectiveness against laboratory-confirmed influenza was 43.5% in pregnant women and 31.4% in infants. Conclusion Maternal influenza vaccination with QIV in pregnancy reduced the odds of pregnant women and their infants to develop influenza. Clinical trial registration www.clinicaltrials.gov identifier is NCT04723771.

Cost-Effectiveness and Burden of Disease for Adjuvanted Quadrivalent Influenza Vaccines Compared to High-Dose Quadrivalent Influenza Vaccines in Elderly Patients in Spain.

Influenza is a contagious respiratory disease that causes severe illness and death, particularly in elderly populations. Two enhanced formulations of quadrivalent influenza vaccine (QIV) are available in Spain. Adjuvanted QIV (aQIV) is available for those aged 65+ and high-dose QIV (HD-QIV) for those aged 60+. In this study, we used a health economic model to assess the costs and outcomes associated with using aQIV or HD-QIV in subjects aged 65+. Using aQIV instead of HD-QIV to vaccinate an estimated 5,126,343 elderly people results in reductions of 5405 symptomatic cases, 760 primary care visits, 171 emergency room visits, 442 hospitalizations, and 26 deaths in Spain each year. Life-years (LYs) and quality-adjusted LYs (QALYs) increases by 260 and 206, respectively, each year. Savings from a direct medical payer perspective are EUR 63.6 million, driven by the lower aQIV vaccine price and a minor advantage in effectiveness. From a societal perspective, savings increase to EUR 64.2 million. Results are supported by scenario and sensitivity analyses. When vaccine prices are assumed equal, aQIV remains dominant compared to HD-QIV. Potential savings are estimated at over EUR 61 million in vaccine costs alone. Therefore, aQIV provides a highly cost-effective alternative to HD-QIV for people aged 65+ in Spain.

Cost-effectiveness analysis of quadrivalent seasonal influenza vaccines in Beijing: A modeling analysis

BackgroundSince 2007, Beijing has offered a free trivalent influenza vaccine (TIV) for residents aged ≥ 60 years and school students. The quadrivalent influenza vaccine (QIV) was administered to school children in 2018 and will be administered to elderly adults in the future. In addition, health care workers (HCWs) who are involved in the prevention and control of COVID-19 were included in the program in 2020. This study aimed to analyze the cost-effectiveness of a comprehensive list of combined strategies of TIV and QIV for school children, elderly adults, and HCWs to identify the most cost-effective strategy. MethodsA decision tree was developed to compare 1-year outcomes of TIV vs. QIV in three risk groups: school children, elderly adults, and HCWs. The outcome was incremental cost per quality-adjusted life-year (QALY). Probabilistic sensitivity analyses and scenario analyses were developed to assess the robustness of the results. ResultsFrom the perspective of society, this study found that the introduction of QIVs can be cost-effective for any and all targeted groups with a willingness-to-pay threshold of 3-fold GDP per capita. Among all programs, program H (all school children, elderly adults, and HCWs received the QIV) showed a 79% probability of being cost-effective with an incremental cost-effectiveness ratio (ICER) of 13,580 (95% CI: 13,294, 13,867) US$/QALY and was the preferred option in the base case scenario. ConclusionThe introduction of QIVs to school children, elderly adults, or HCWs is likely to be cost-effective, either separately or collectively. The introduction of QIV to school children, elderly adults, and health care workers simultaneously showed the highest probability of being cost-effective and was the preferred option.

Postmarketing safety surveillance of high-dose quadrivalent influenza vaccine: Reports to the Vaccine Adverse Event Reporting System

On November 4, 2019, the Food and Drug Administration approved high-dose quadrivalent influenza vaccine (Fluzone High-Dose Quadrivalent; QIV-HD) for active immunization for the prevention of influenza disease in individuals 65 years of age and older. A prelicensure randomized, active-controlled, modified double-blind trial did not reveal any major differences in adverse events following QIV-HD versus Fluzone High-Dose (trivalent). To improve our understanding of the safety profile of QIV-HD, we reviewed and summarized reports of adverse events after QIV-HD to the Vaccine Adverse Event Reporting System (VAERS). From July 30, 2020 through June 30, 2021, VAERS received 2,122 reports after QIV-HD. The vast majority (2,018; 95.1%) were non-serious and included events that had been observed in the prelicensure clinical trial, such as injection site reactions, fever, headache, and nausea. The most common serious events included Guillain-Barré syndrome, cellulitis or other local reactions, constitutional signs/symptoms (e.g., fever), and cardiovascular events. Our review did not reveal any new safety concerns. This information may enable policy makers, health officials, clinicians, and patients to make a more informed decision regarding vaccination strategies.

Lineage-matched versus mismatched influenza B vaccine effectiveness following seasons of marginal influenza B circulation

BackgroundSeveral countries have recently transitioned from the trivalent inactivated influenza vaccine (TIV) to the quadrivalent inactivated influenza vaccine (QIV) in order to outweigh influenza B vaccine-mismatch. However, few studies thus far evaluated its benefits versus the TIV in a systematic manner. Our objective was to compare the QIV VE with lineage-mismatched TIV VE. MethodsWe estimated the 2015–2016, 2017–2018, 2019–2020 end-of season influenza B VE against laboratory-confirmed influenza-like illness (ILI) among community patients, using the test-negative design. VE was estimated for pre-determined age groups and for moving age intervals of 15 years. ResultsSince 2011–2012 season, alternate seasons in Israel were dominated by influenza B circulation. Compared with the lineage-mismatched TIV used during the 2015–2016 and 2017–2018 seasons, the 2019–2020 QIV showed the highest all-ages VE, with VE estimates of 56.9 (95% CI 30.1 to 73.4), 16.5 (95% CI –22.5 to 43.1) and −25.8 (95% CI −85.3 to 14.6) for the 2019–2020, 2017–2018 and 2015–2016 seasons, respectively. The 2019–2020 VE point estimated were the highest for the 0.5–4, 5–17 and 18–44 years age groups and for more 15-year age intervals as compared to the other seasons. ConclusionsOur results support the rapid transition from the TIV to the QIV.